@article{62ef171d26334d4eacd0572258b4b972,
title = "Disrupted NOS2 metabolism drives myoblast response to wasting-associated cytokines",
abstract = "Skeletal muscle wasting drives negative clinical outcomes and is associated with a spectrum of pathologies including cancer. Cancer cachexia is a multi-factorial syndrome that encompasses skeletal muscle wasting and remains understudied, despite being a frequent and serious co-morbidity. Deviation from the homeostatic balance between breakdown and regeneration leads to muscle wasting disorders, such as cancer cachexia. Muscle stem cells (MuSCs) are the cellular compartment responsible for muscle regeneration, which makes MuSCs an intriguing target in the context of wasting muscle. Molecular studies investigating MuSCs and skeletal muscle wasting largely focus on transcriptional changes, but our group and others propose that metabolic changes are another layer of cellular regulation underlying MuSC dysfunction in cancer cachexia. In the present study, we combined gene expression and non-targeted metabolomic profiling of myoblasts exposed to wasting conditions (cancer cell conditioned media, CC-CM) to derive a more complete picture of the myoblast response to wasting factors. After mapping these features to annotated pathways, we found that more than half of the mapped pathways were amino acid-related, linking global amino acid metabolic disruption to conditioned media-induced myoblast defects. Notably, arginine metabolism was a highly enriched pathway in combined metabolomic and transcriptomic data. Arginine catabolism generates nitric oxide (NO), an important signaling molecule known to have negative effects on mature muscle. We hypothesize that tumor-derived disruptions in Nitric Oxide Synthase (NOS)2-regulated arginine catabolism impair differentiation of MuSCs. The work presented here further investigates the effect of NOS2 overactivity on myoblast proliferation and differentiation. We show that NOS2 inhibition is sufficient to rescue wasting phenotypes associated with inflammatory cytokines. Ultimately, this work provides new insights into MuSC biology and opens up potential therapeutic avenues for addressing disrupted MuSC dynamics in cancer cachexia.",
keywords = "Cancer cachexia, IFNγ, Myoblast, NOS2, Nitric oxide, TNFα",
author = "Arneson-Wissink, {Paige C.} and Doles, {Jason D.}",
note = "Funding Information: The authors wish to thank members of the Doles lab for helpful discussions and manuscript suggestions (Rebecca Schmitt, PhD, Aneesha Dasgupta, PhD, and Alexandra Ducharme). J.D. was supported by the National Institutes of Health (award #s: R00AR66696, R35GM128594), Mayo Clinic start-up funds, Career Development Awards from the Mayo Clinic SPORE in Pancreatic Cancer (NIH/National Cancer Institute (NCI) CA102701) and the American Association for Cancer Research/Pancreatic Cancer Action Network, and the Glenn Foundation for Medical Research. P.C.A-W was supported by the Mayo Clinic Regenerative Sciences Training Program (RSTP). Metabolomics studies were made possible by the Mayo Clinic Metabolomics Resource Core through NIH/National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) U24DK10049 originating from the NIH Director's Common Fund. The Mayo Clinic Genome Analysis Core provided experimental support for the RNA sequencing study. Lung adenocarcinoma cell lines were a generous gift from Yanan Yang, PhD. Funding Information: The authors wish to thank members of the Doles lab for helpful discussions and manuscript suggestions (Rebecca Schmitt, PhD, Aneesha Dasgupta, PhD, and Alexandra Ducharme). J.D. was supported by the National Institutes of Health (award #s: R00AR66696 , R35GM128594 ), Mayo Clinic start-up funds, Career Development Awards from the Mayo Clinic SPORE in Pancreatic Cancer ( NIH /National Cancer Institute ( NCI ) CA102701 ) and the American Association for Cancer Research / Pancreatic Cancer Action Network , and the Glenn Foundation for Medical Research . P.C.A-W was supported by the Mayo Clinic Regenerative Sciences Training Program ( RSTP ). Metabolomics studies were made possible by the Mayo Clinic Metabolomics Resource Core through NIH /National Institute of Diabetes and Digestive and Kidney Disease ( NIDDK ) U24DK10049 originating from the NIH Director's Common Fund. The Mayo Clinic Genome Analysis Core provided experimental support for the RNA sequencing study. Lung adenocarcinoma cell lines were a generous gift from Yanan Yang, PhD. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = oct,
day = "1",
doi = "10.1016/j.yexcr.2021.112779",
language = "English (US)",
volume = "407",
journal = "Experimental Cell Research",
issn = "0014-4827",
publisher = "Academic Press Inc.",
number = "1",
}